Download Corneal Stromal Dystrophies: A Clinicopathologic Review

Corneal Stromal Dystrophies: A Clinicopathologic Review
Emily S. Birkholz, MD, Nasreen A. Syed, MD, and Michael D. Wagoner, MD, PhD
July 29, 2009
INTRODUCTION
Corneal stromal dystrophies are a group of inherited disorders of the cornea that are caused by progressive
accumulation of deposits within the stroma. These deposits are not caused by inflammation, infection, or trauma, but
by genetic mutations that lead to abnormal proteins resulting in the accumulation of insoluble material within the
stroma. The disorders may or may not affect vision and may or may not be symmetrical. They usually present in the
second to third decade of life (1). Table 1 lists the different corneal stromal dystrophies. The major corneal
dystrophies include lattice, granular, and macular dystrophy. A simple mnemonic for memorizing the corneal
stromal dystrophy, the composition of the stromal deposit, and the method of staining these deposits is listed in
Table 2. This mnemonic is well known by ophthalmology residents around the country.
Table
1:
Corneal
Stromal
Dystrophies
•
•
•
•
•
•
•
•
Table
2:
Mnemonic
for
remembering
corneal
stromal
dystrophies
• Marilyn — Macular Dystrophy
• Monroe — Mucopolysaccharide
• Always — Alcian Blue stain
• Gets — Granular Dystrophy
• Her — Hyaline
• Man in — Masson Trichrome stain
• Los— Lattice Dystrophy
• Angeles — Amyloid
• California — Congo Red
Lattice
Granular
Avellino
Macular
Gelatinous Droplike dystrophy
Schnyder Crystalline Corneal
Dystrophy (SCCD)
Francois-Neetens Fleck
Dystrophy
Congenital Hereditary Stromal
Dystrophy
GENETICS
Four corneal dystrophies including granular, lattice, Avellino, and Reis-Bückler have been linked to a mutation
in the Transforming Growth Factor Beta 1 gene (TGFβ1), also known as the BIGH3 gene. This gene, located on
chromosome 5q31 codes for keratoepithelin, a protein secreted by corneal epithelium. This protein acts as an
adhesion protein and is present in normal stroma. Being a small protein roughly the size of albumin, it has the
capability to diffuse through the corneal stroma. When a mutation in the BIGH3 gene occurs, the keratoepithelin
molecule is abnormal and accumulation of the insoluble protein occurs in the cornea (1). To date, thirty different
mutations have been identified in the BIGH3 gene (2). Interestingly, the BIGH3 gene mutation was discovered in
part at the University of Iowa. A group of researchers and clinicians including Edwin M. Stone, Robert Folberg, and
Jay H. Krachmer mapped Avellino, granular, and lattice dystrophy to chromosome 5q in 1994 (3).
LATTICE CORNEAL DYSTROPHY
Lattice corneal dystrophy (LCD) is the most common of the corneal stromal dystrophies. It is an autosomal
dominant, bilateral disease that typically presents toward the end of the first decade of life with symptoms of
recurrent corneal erosions and decreased vision. It is characterized by lattice lines which are linear, radially oriented,
branching refractile opacities described as "glass like" located in the anterior stroma (See Figure 1A and 1B). These
lattice lines are usually restricted to the central cornea, sparing the periphery (1). Many patients with LCD will
require surgical intervention for treating recurrent erosions and decreased vision. If the disease is located anteriorly
in the stroma, patients can often be successfully treated with phototherapeutic keratectomy (PTK). Some require
corneal transplantation. Because keratoepithelin, the protein produced by the BIGH3 gene, is produced mostly from
corneal epithelium, the disease recurs in corneal grafts.
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Figure
1.
Lattice
corneal
dystrophy
A.
Left
eye
on
retroillumination
demonstrating
anterior
stromal
deposits
in
lattice
corneal
dystrophy
B.
Left
eye
with
higher
power
showing
linear
anterior
stromal
deposits.
C.
H&E
stain
of
cornea
with
lattice.
Note
pink
amorphous
deposits
in
stroma
D.
A
closer
view
of
the
pink,
amorphous
deposits
E.
Congo
red
stain,
highlighting
amyloid
F.
Apple‐green
birefringence
of
amyloid
with
cross‐
polarization.
2
LCD is associated with a genetic mutation in the BIGH3 gene, resulting in deposits of amyloid within the anterior
corneal stromal. Histopathologically, these deposits appear as amorphous pink deposits on hematoxylin and eosin
(H&E) stains (See Figure 1C and 1D). Because the deposits consist of amyloid, they stain with Congo red stain and
classically show apple green birefringence on cross-polarization (See Figure 1E and 1F) (1).
Five subtypes of LCD have been identified. LCD type I is the classic form of LCD caused by a mutation in the
BIGH3 gene resulting in isolated amyloid deposition in the cornea. LCD type II is a systemic amyloidosis affecting
the skin, cranial nerves and cornea known as Meretoja syndrome. This presents in early adulthood with peripheral
neuropathies, cranial neuropathies, hound-like facies, dry skin, blepharochalasis, protruding lips, and corneal lattice
lines. This type has been linked to the gelsolin gene on chromosome 9, which encodes for an amyloid precursor
protein which functions to remove actin from sites of injury and inflammation. LCD types III and IIIA present later
in life with thicker linear opacities in the mid corneal stroma. LCD type III is an autosomal recessive condition
presenting in the 7th-8th decade of life in which erosions rarely occur, and LCD IIIA is an autosomal dominant
disease associated with a mutation in the BIGH3 gene that frequently leads to erosions and decreased vision in the
4th-5th decade of life. LCD type IV has been described as a late onset dystrophy occurring in the deep stroma, also
associated with the BIGH3 gene (4)
Figure
2.
Type
I
granular
corneal
dystrophy.
A.
Slit
lamp
photo
of
Granular
Corneal
Dystrophy
B.
Note
the
“crumb‐
like”
stromal
deposits
with
clear
intervening
stroma.
C.
H&
E
stain
of
cornea
showing
eosinophilic
“rock
candy
D.
Hyaline
material
stains
bright
red
with
Masson‐
like”
hyaline
deposits
in
stroma
Trichrome
GRANULAR CORNEAL DYSTROPHY
Granular corneal dystrophy (GCD) is a bilateral, autosomal dominant disease associated with a mutation in the
BIGH3 gene that leads to the deposition of a hyaline material in the corneal stroma. It typically presents early in the
first decade of life with gray-white, "crumb-like" opacities in the anterior to mid stroma. These opacities are discrete
deposits located centrally, with clear cornea located in the periphery and clear cornea between deposits (See Figure
2A and 2B). The disease is typically asymptomatic early on, but with time the opacities can coalesce and lead to
decreased vision. Recurrent corneal erosions can occur in GCD but at a lower incidence than in LCD (1,4).
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Treatment early on in the disease process is often observation only. However, as the disease progresses, PTK and
corneal transplantation may be needed to improve vision and erosion symptoms. Like LCD, the disease can recur in
corneal grafts.
Histopathologically the opacities are eosinophilic deposits often described as "rock candy like" in the anterior
stroma made of a hyaline-like material. With time, the deposits progress into the deeper corneal stroma. The hyaline
material stains bright red with Masson trichrome stain (See Figure 2C and 2D).
Figure
3.
Type
II
granular
corneal
dystrophy
‐
Avellino
dystrophy
A.
Avellino
dystrophy
showing
lattice
like
and
granular
like
deposits
in
corneal
stroma
B.
MassonTrichrome
stain
demonstrating
anterior
stromal
hyaline
deposits
C.
Congo
red
stain
showing
pink,
amorphous
amyloid
deposits
in
the
same
corneal
specimen.
D.
Cross‐polarization
reveals
apple
green
birefringence
indicating
amyloid.
Three types of GCD have been described. GCD Type I is the classic form of GCD as described above. GCD
Type II, also known as Avellino, or granular-lattice corneal dystrophy, is an autosomal dominant disease linked to a
mutation in the BIGH3 gene that leads to a deposition of both hyaline and amyloid in the corneal stroma. Typically,
patients present in their second decade with granular opacities like in GCD, but later in the disease process develop
lattice lines as well (See Figure 3A and 3B). Histopathologically, the cornea will have stromal deposits that stain red
with Masson Trichrome, indicating the presence of hyaline (See Figure 3C). In addition, staining with Congo red
will demonstrate apple-green birefringence on cross-polarization indicating amyloid (See Figure 3D). The disease
was thought to have originated from a family in Avellino, Italy. However, GCD type II has now been reported in
patients from many other countries as well (2,4).
GCD type III, also known as Reis Bückler or Corneal Dystrophy of Bowman's type I, is an autosomal dominant
disease considered by some to be a superficial variant of GCD type I. Patients typically present with normal corneas
at birth but develop painful recurrent erosions, opacification, and vision loss within the first decade of life. This
disease has also been linked to the BIGH3 gene (2,4). Histopathology reveals anterior stromal and subepithelial
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deposits of hyaline like material which disrupt and often replace Bowman's layer (See Figure 4A and 4B). The
hyaline like material consists of rod like bodies which can best be seen with electron microscopy (1).
Figure
4.
Type
III
granular
corneal
dystrophy
‐
Reis‐Buckler
dystrophy
A.
H&E
of
Reis
Bückler
showing
destruction
of
Bowman’s
layer
and
irregular
epithelium
B.
Masson
Trichrome
stain
demonstrating
epithelial
staining
MACULAR CORNEAL DYSTROPHY
Macular corneal dystrophy (MCD) is an autosomal recessive disease caused by a mutation on chromosome 16
that leads to a defect in the synthesis of keratan sulfate, the major glycosaminoglycan of the cornea. It is the least
common of the major corneal stromal dystrophies, but thought to be the most severe. Although MCD is less
common worldwide than LCD or GCD, it is the most common of the corneal stromal dystrophies in some areas such
as Iceland and Saudi Arabia (5). Gray-white anterior stromal lesions similar to GCD appear in the cornea in the first
decade of life. Unlike GCD, however, there is stromal haze between the deposits, and the entire cornea from limbus
to limbus is often involved (See Figure 5A and 5B). Patients typically develop severe visual loss by the second to
third decade of life due to diffuse corneal haze. PTK can be performed in some early cases of MCD. However, this
condition is generally not as amenable to PTK as lattice or granular dystrophy and often requires corneal
transplantation for treatment (6). Recurrence in grafts is less common in MCD than with granular or lattice
dystrophy (1,2,4,5).
The stromal deposits in MCD are composed of mucopolysaccharides that accumulate within the endoplasmic
reticulum of keratocytes of the corneal stroma, extracellularly between stromal lamellae, and underneath and within
the corneal epithelium (5). These deposits stain blue with Alcian blue (See figure 5C and 5D) (1).
Three subtypes of MCD have been described based on the presence or absence of immunoreactive keratan sulfate
within various tissues. Type I does not have immunoreactive keratan sulfate in the corneal stroma, keratocytes, sera
or cartilage, and is the most common variant of MCD worldwide. Type IA lacks keratan sulfate in the stroma, sera,
and cartilage, but has detectable levels inside keratocytes. Type II has keratan sulfate present at much reduced levels
in the stroma, keratocytes, sera and cartilage (5).
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Figure
5.
Macular
corneal
dystrophy
A.
Slit
lamp
photo
of
macular
corneal
dystrophy.
B.
Note
the
haze
between
the
corneal
stromal
deposits
C.
H&E
of
cornea
with
macular
dystrophy.
Note
anterior
stromal
deposits
and
Bowman’s
layer
disruption
D.
Mucopolysaccharide
deposits
within
keratocytes
highlighted
with
Alcian
Blue
stain
SCHNYDER CORNEAL CRYSTALLINE DYSTROPHY (SCCD)
SCCD is an autosomal dominant, bilateral corneal stromal dystrophy linked to a genetic mutation on
chromosome 1. The resulting metabolic defect of corneal keratocytes leads to crystalline lipid deposition. Clinically
the disease presents with a ring-shaped accumulation of fine needle shaped polychromatic crystal deposits within
Bowman's layer and the anterior stroma, and is often associated with a presenile peripheral lipid arcus (See Figure
6A and 6B). The disease typically presents in the first decade of life, and typically does not cause vision loss until
past middle age. However, most patients by the seventh decade may require surgical treatment including corneal
transplantation or PTK. Recurrences in grafts can occur. The disease has been linked with hyperlipidemia and genu
valgum in some patients (4, 7).
Histopathologically, birefringent cholesterol crystals composed of phospholipids and cholesterol deposit within
keratocytes, in Bowman's layer, and between stromal lamellae. These lipid deposits stain red with Oil-Red-O stain.
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Figure
6.
Schnyder
corneal
crystalline
dystrophy
A.
Slit
lamp
photo
of
Schnyder
Corneal
Crystalline
Dystrophy.
B.
Centrally
located
crystalline
deposits
C.
H&E
of
cornea
with
SCCD
D.
Oil
Red
O
stain
highlights
cholesterol
crystals
which
appear
red.
OVERVIEW: CORNEAL STROMAL DYSTROPHIES
EPIDEMIOLOGY
• Autosomal Dominant disease
o Granular corneal dystrophy (GCD)
o Lattice corneal dystrophy (LCD)
o Schnyder’s crystalline corneal dystrophy
(SCCD)
• Autosomal Recessive
o Macular corneal dystrophy (MCD)
• Present in 1st - 3rd decade of life
SIGNS
• Recurrent erosions
• Bilateral corneal stromal deposits in various patterns
o Crumb-like deposits for GCD
o Lattice lines for LCD
o Diffuse haze and stromal deposits for MCD
o Central crystalline deposits with surrounding
Arcus for SCCD
SYMPTOMS
• Initially none
• Bilateral recurrent erosions causing pain, tearing,
and foreign body sensation
• Over time can have decreased vision
TREATMENT
• Observation
o Early in course
o Lubrication
o Manage recurrent erosions with bandage contact
lens and topical antibiotic (erythromycin ointment
or 3rd-4th generation fluoroquinolone)
• Phototherapeutic Keratectomy
• Corneal Transplantation
o If recurrent erosions severe or if decreased vision
o Recurs in grafts
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REFERENCES
1. Keefe KS, Milman T, Rodrigues MM, Hidayat AA. Conjunctival and Corneal Pathology. Albert and Jakobiec's
Principles and Practice of Ophthalmology, 3rd edition. Saunders. 2008: 3592-3595.
2. Poulaki V, Colby K. Genetics of anterior and stromal corneal dystrophies. Seminars in Ophthalmology, 2008;
23: 1,9-17
3. Stone EM, et al. Three autosomal dominant corneal dystrophies map to chromosome 5q. Nature genet. 1994; 6:
47-51.
4. Bron AJ. Genetics of the Corneal Dystrophies: What we have learned in the past twenty five years. Cornea
2000; 19(5): 699-711.
5. Al-Swailem SA, Al-Rajhi AA, Wagoner MD. Penetrating Keratoplasty for Macular Corneal Dystrophy.
Ophthalmology 2005;112: 220-224.
6. Badr IA, Wagoner MD. Phototherapeutic Keratectomy for Macular Corneal Dystrophy. J Refract Surg
1999;15:481-484.
7. Shearman AM, Hudson TJ, Andresen JM, et al. The gene for Schnyder's crystalline corneal dystrophy maps to
human chromosome 1p34.1p36. Hum Mol Genet 1996;5:1667-72.
suggested citation format:
Birkholz ES, Syed NA, Wagoner, MD. Corneal Stromal Dystrophies: A Clinicopathologic Review.
EyeRounds.org. August 4, 2009 [cited --insert today's date here -- ]; Available from:
http://www.eyerounds.org/cases/43-corneal-stromal-dystrophies.pdf
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